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of A thesis submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Master of Science in Chemistry 2015 Abstract Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative

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Benzo-1,3,2-dithiazole-1,1-dioxides (BDTs) are novel 5-membered heterocycles bearing an internal sulfur-nitrogen bond and are structurally similar to benzoisothiazolones (BiTs). A new method for the synthesis of these molecules was developed and a series of BDTs were made and studied as potential BiT alternatives in organocatalytic redox-coupled, metal catalyzed dehydrative bond constructions. The BDTs could be synthesized via generation of a sulfenyl chloride from o-benzylthiobenzene sulfonamide followed by condensation with the adjacent nitrogen. The BDTs could react with carboxylic acids in a redox dehydration with triphenylphosphine or triethyl phosphite to generate BDT-derived thioesters. This reaction worked well with aliphatic acids and to a lesser extent with aromatic acids. These thioesters could then undergo coupling with boronic acids to give S-arylated products, but the reaction between BDT-derived thioester and amine gave only hydrolysis of the thioester with no desired amide formation. Finally, the reduced form of BDT, the o-mercaptobenzene sulfonamide, could be oxidized back to the BDT at temperatures above 100 oC in the presence of a variety of oxidants. Future work will be de done to assess the utility of BDTs as organocatalysts in redox dehydration reactions as well as explore other alternative applications.

Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative

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First and foremost, I would like to thank my advisor, Dr. Lanny Liebeskind, for all of the help, support and guidance he has given me during my graduate school career. With his help and encouragement, I have experienced significant growth as a chemist, a scientist, and most importantly a person. He has been very supportive in all of my decisions and I will always have a deep gratitude for his mentorship and look back on these years fondly.

I would also like to thank my committee members, Dr. Huw Davies and Dr. Chris Scarborough for their advice and support. Their criticisms helped me focus my research and, eventually, got me to the point where I had a nice story to tell about my work. My gratitude also goes out to Dr. Dennis Liotta, Dr. Simon Blakey and Dr. Frank McDonald for their efforts in the classroom to help me further my education.

Next, I would like to thank all of the Liebeskind lab members that I had the privilege to work alongside over the past 2 and a half years. Your advice was invaluable and I attribute much of what I have learned in lab to the support of my coworkers. I truly would not have been able to get to this point without your help.

I would like to thank my family for their unwavering love support as well as their genuine interest in trying to learn about my work. Finally, I would like to thank my girlfriend Emily Ryan for constantly standing next to me, helping me make important decisions, and

Introduction Benzoisothiazolones (BiTs) are well known 5-membered heterocycles containing an internal sulfur-nitrogen bond and are widely used in pharmaceutical and agricultural industries.

In particular, it has been shown that specific BiT derivatives exhibit antifungal and antimicrobial activities,1,2 can selectively inhibit phosphatase enzymes,3,4 and possess anti-HIV and anti-cancer properties.5,6 Because of their biological importance, the synthesis of activity of BiTs has been extensively studied.

As illustrated in Figure 1, a number of methods to construct benzoisothiazolones have been reported. These methods include: (a) condensation of 2-(chlorocarbonyl)phenyl hypochlorothioite and amine,7 (b) treatment of 2-(t-butylthio)-5-nitrobenzamide with trimethylsilyl chloride,8 (c) cyclization of t-butyl sulfoxides9 and (d) copper-catalyzed

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and some wasted reagent, benzoisothiazolones can be obtained in high yields and with a wide variety of structural variation. Further, BiTs are synthetically useful molecules that can react with reducing agents to give o-mercaptobenzamides,11 thiols to give unsymmetrical disulfides,12,13 as well as a variety of phosphorus, carbon and sulfur nucleophiles to give other products.11 Another interesting transformation of BiTs has been described by Villalbos8 and then Srogl.14 In 2008, she reported the conversion of BiTs into thioesters via redox dehydration of carboxylic acids using an organophosphine reductant. This reaction is analogous to the thioesterification of disulfides previously described by Mukaiyama.15 A direct comparison of these two reactions is given in Scheme 1. Both are redox reactions in which sulfur is reduced to a thiol which goes on to generate thioester by reacting with an acyloxyphosphonium intermediate and resulting in oxidation of a phosphine to phosphine oxide (Scheme 2). The major disadvantage in Mukaiyama’s procedure is the loss of half of the disulfide as thiol. The BiT reaction does not suffer from this drawback, and as we will see, the BiT-derived thioesters are

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One interesting application in which BiT-derived thioesters are important is the copper catalyzed aerobic ketone synthesis from thioesters and boronic acids as described by Liebeskind.16 In this reaction, ortho mercaptobenzamides are involved in a coupling reaction with boronic acids to synthesize a variety of peptidyl-based and other synthetically useful ketones (Scheme 3).17 A major limitation of this procedure is the need for a sacrificial equivalent of boronic acid in order to trap (as a thioether) any thiolate generated under the reaction conditions. This drives the reaction forward by facilitating the release of the copper catalyst that was previously tied up as a stable copper thiolate. As a result, a full equivalent of the S-arylated ortho mercaptobenzoic acid amide is obtained as an undesired side product. In an effort to overcome this limitation, the Liebeskind group became interested in the oxidative recycle of ortho mercaptobenzoic acid amides to BiTs as a way to “internally” trap thiolate without the need for wasted reagents or the production of side products. In recent results from Matthew Lindale18 this goal was achieved via the use of N-methylimidazole (NMI) as a ligand on

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The Liebeskind group now envisioned a fully catalytic protocol for dehydrative bond construction by linking thioesterification and the coupling of BiT-derived thioesters, shown in Schemes 2 and 4, through an oxidative recycle of the BiT. This reaction can also be generalized to reaction partners beyond boronic acids and the full catalytic cycle is described in Figure 2.

This catalytic cycle takes advantage of BiTs as redox organocatalysts for the construction of amides, esters and ketones. The cycle begins with the generation of a BiT-derived thioester in a Mukaiyama-like dehydration as described above. Results from the Liebeskind lab have also significantly improved this protocol by replacing organophosphine reductants with triethyl phosphite. The use of triethylphosphite both eliminates the need for more reactive organophosphines and dramatically simplifies the reaction workup since P(OEt)3 is converted to water soluble OP(OEt)3 during the reaction. The synthesis of a variety of thioesters synthesized by this method has been described by Leighann Lam.20 The next step consists of a reaction between the thioester and a nucleophilic reaction partner to generate the acylated product, an

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reaction partner determines the product outcome (i.e. amine, alcohols and boronic acids will give rise to amides, esters and ketones respectively), making the catalytic cycle generalizable to a wide range of substrates beyond the scope described thus far. The final step of the cycle is copper catalyzed aerobic regeneration of the BiT. To date, a variety of amides have been synthesized using this procedure, and work is underway to extend the utility of this catalytic reaction into making esters and ketones.

Another class of molecules bearing an internal sulfur-nitrogen bond is benzo-1,3,2dithiazole-1,1-dioxides, here referred to as BDTs. The structure of the BDT (Figure 3) is

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Further, since sulfonamides are stronger electron withdrawing groups, we can predict that the sulfenamide functional group (S-N bond) on the BDT is more electrophilic than that of BiTs and as a result should react more rapidly with nucleophiles. If this is true, then BDTs may be useful redox organocatalysts.

Despite their structural similarities to BiTs, a widely used and versatile molecule, surprisingly little work can be found in the literature on BDTs, and the only known information is described in two patents.7,21 The first patent discusses the synthesis of 5-nitro-1,3,2-dithiazoledioxides, a molecule with the same internal sulfur-nitrogen-sulfur bonds. The second describes the synthesis of N-aryl BDTs from a condensation reaction between 2chlorosulfonyl)phenyl hypochlorothioite and amines as shown in Scheme 5. The patent also describes BDTs as potential medicaments but does not give any specific details beyond the synthesis of a small sample of molecules. With relatively little known about BDTs, there is a lot of potential for the discovery of new and interesting chemistry. Here we describe a study of BDTs as potential alternatives to BiTs in some known catalytic systems.

A general synthetic route to BDTs was explored, and the BDTs were then studied as redox organocatalysts in place of BiTs. The study took place in three parts: (1) thioesterification of carboxylic acids with BDTs and both phosphine and phosphite reducing agents, (2) reaction of amines and boronic acids with BDT-derived thioesters and (3) oxidative regeneration of the

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done to examine the use of BDTs as redox organocatalysts for the synthesis of interesting and useful organic molecules such as amides, ketones and esters.

Results / Discussion There are a variety of methods we could envision for the successful synthesis of BDTs.

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